Rapamycin and demethoxyrapamycin are two members of a growing class of macrolide natural products possessing marked immunosuppressive properties. Recently, several groups have focused on the preparation of both modest and advanced fragments of the polyketide skeleton, culminating in three total syntheses of rapamycin. In addition, several groups have prepared semi-synthetic analogs of rapamycin to improve upon its impressive therapeutic profile as well as to gain insight into the as-yet-unresolved mechanism of action.
To date, four research groups have reported the discovery and isolation of a 220 kDa protein which is thought to be the direct intracellular target of the rapamycin-FKBP complex. This protein shares structural homology with a number of known lipid kinases although its specific role in signal transduction and immunosuppression remains unclear. It has, however, been established that rapamycin interferes with a Ca.sup.2+ -independent signaling pathway emanating from the IL-2 receptor, thus prohibiting the progression of activated T cells from the G1 to the S phase of the cell cycle, perhaps via indirect inhibition of a cyclin dependent kinase specifically required for this transition.
There is a need for improved synthetic methods for the preparation of rapamycins. This invention is directed to this important end.